Package and process



Nov." 19, 1957 e. c. CQLOVOS I PACKAGE AND PROCESS ned iman 21, 955

I r@ fl////////////////// v INVENTOR GA-'0.964' C. 604 eros 'BY ATTORNEY PACKAGE AND PROCESS George C. olovos, Kalamazoo Township, Kalamazoo County, M ch., assignor to The Upjohn Company, Kalamazoo, Mch., a corporation of Michigan Application March 21, 1955, Serial No. 495,567

15 Claims. (CI. 206-46) This invention relates to a novel package and to a process for making the same and is particularly directed to a sterile, single-dose, multiple-unit-applicator-package of medicamen't, and to a method for making the same.

lt has been customary heretofore to dispense medicinal preparations, such as those used for ophthalmic purposes in multiple-dosage units, such as metal tubes and dropper bottles. This method of dispensing has the disadvantage that the tip of the tube and the tip of the dropper were not sterile and even if they had been, could not be maintained in a sterile condition once opened. Application of nedicaments in this wise, therefore, tended to promote collateral `infection. It is also known to dispenso medicinal preparations in unit-dosage containers but none of 'the known expedients of this kind have been adapted to or useful in the dispensing of medicinal preparations, such as ophth'almic medicaments, where both the contents and the package are required to be in a sterile condition. Nor has it been heretofore possible efiectively to sterilize unit-dosage packages, especially if the packaging material and/or the medicament were sensitive to the usual methods of sterilization.

lt is an object of this invention to provide ways and means whereby medicinal preparatons which must be kept `sterile can be eflectively dispensed in unit-dosage applicator-p'ackages. It is 'a further `object of the invention to provide novl, `sterile, single-dose, multiple-unit packages of medicament and to provide a novel method for making them. It is a further object of the invention to provide 'a process and applicator-package in which both the contents and the package material inside and out are obtained and maintained in a `sterile and :attractive condition. It is a further object to 'provide a process and package in which sterilizing can be effccted with ioni'zing radiation without adverse ettect on any of the Components thereof. Still further objects will become `apparent as the description proceeds.

lt is customary in the art to dispense medicinal preparations` in soft elastic capsules of :such size as to contain a single dose. These capsules are commonly made of gelatin which has been softcned by a suitable plasticizer. Glycerol is commonly used'as the plasticizer.

it has been found, 'according to this invention, that When glycerol-plasticized gelatin'capsules are irradiated with ionizing rays, such` as cathode rays or `gamma rays, the glycerol, notwithstanding that'the temperature elevation due to the `irradiation rarely exceeds about four or five degrees centigrade, is vaporized to such an extent that if the capsules are conned in a transparent envelope, fogging of the envelope sometimes occurs due to the condensation` of glycerol thereon.

It has been found further, according to this invention, that the fogging of the transparent envelopes containing glycerol-plasticized, soft elastic capsules which results after exposure toionizing radiation, can be avoided by interposing 'a film of moisture-impervious material between the inner surface of the 'envelope and the outer surface of the capsules. Thusif the .inner surface of the transparent envelope or the outer surface of the capsule `(or both) is provided with a moisture-impervious tates Patent ;dating `or film, fogging of the transparent -envelope by 'ice glycerol as a result of exposure to ionizing radiation is minimized and/or completely avoided.

It is known that anti-watcr-fogging properties can be imparted to 'transparent films by coating them with wettin'g agents. (See for example U. S. Patents 2,489,026 and 2,'56l.,010.) Unfortunately, these same anti-water fogging coatings have been found to be relatively inetfective in preventing glycerol-fogging due to exposure to ionizing radiation of transparent envelopes containing *glycerol-plasticized, soft elastc, gelatin capsules. The finding of this invention that water-impervious coatings on `the inside surface of such envclopes or on the outside surface of the capsules act to prevent glycerol-fogging, was, therefore, unexpected.

'The invention now may be more fully understood by refer'ing to the accompanying drawing in which:

`Figure l is a plan View of a sterile, single-dose, multipleunit package according to the invention;

Figure' 2 is a plan View of a single-close unit according to the invention; and

Figure 3 is a sectional view taken along line lII-III of Figure 2.

Referring now to the drawing, there is shown in Figure` 1 a plurality of single-close, glycerol-plasticized, soft elastic, gelatin capsules M, each contained in a separate hermetically sealed compartment 12 of a multiple-compartment envelope 14. The envelope 14 is advantageously made from two sheets of transparent, heat-sealable material as wili be more particularly described hereinafter, heat-sealed along the sides as shown at 16 and crosswise at spaced intervals, as shown at 18, to provide 'a separate compartment for each of the single dose nnits. If desired, the edges lo can *be cut or scored, as shown at 20 so that the individual compartments can be torn open readi-ly. i

Referring now to Figu'es 2 and 3, there will be found enlarged detailed views of a single-close capsule, according to the invention. The single-close capsule consists of a body portion 26 which is approximately twice as long as it is wide, having an elongated tip Zt projecting from one end along the major axis. The unit is formed of two sheets of glycerol-plasticized gelatin, united entirely around the circurnference, as shown at Siti, to form an ovate tubular capsule. The glycerol-plasticized gelatin sheets are cut, filled, and united according to any of the well known methods for forming soft elastic capsules. v

The single-desc capsules thus prepared make it possible easily and effectively to administer a single close of sterile medicament. All that is necessary is to clip the end 'from the elongated tip 23 and squeeze the body portion 26 between the thumb and orefinger. in this way, a fine stream of medicament is exuded from 'the clipped tip onto or into the aected part, such as the eye or eyes. The amount of material and the size of the unit are such as to provide only so much material as is needed for a single application. Once the application is made, the whole unit can be disposed of, thus insuring against contamination and collateral infection.

In order to provide effective discharge of so small a quantity of medicament, the unit is designed with its body portion having a length which will fit cornfortably in the normal area of contact between the thurnb and forefinger of an individual, say, between about one-half and one and one-half centimeters. The width of the body is between about two and three-fourths the length of the body and the cross section is ovate, advantageously with a thickhess which `is approxinately one-half the width. With a unit of proper shape, as described, the body portion can be held comfortably between the thumb and forefinger and rolled back .and forth as necessary effectively to squeeze outthe medicament.

The elongated tip 28 is advantageously circularor ovate in cross section and of substantially smaller diameter than the minimum diameter of the body portion. The tip 28 may, if desired, be tapered so that it is wider near the body portion 26 than at the end so that the opening can be made larger by clipping the tip nearer the body 26. suitably the angle of taper may be ten degrees or less. A taper of about four degrees has been found satisfactory.

The side edges 52 of the tip merge gradually into the bottom portion 26 forming between the body and the tip a truncated surface 54 unitary with both the body 26 and tip 52, the elements of which truncated surface have an ogee curvature as shown at 54.

The capsules 10 are formed from glycerol-plastcized gelatin sheets in capsulatng machines having suitably shaped dies. The procedure used and design of such machines are well known to those skilled in the art and need not be described herein. Similarly the composition and preparation of glycerol-plasticzed gelatin sheets for this purpose are also well known in the art and need not be described. It may be given by way of example, however, that a suitable formulation of glycerol-plasticized gelatin for use in accordance with the present invention, contains 38 percent gelatin, 29 percent glycerol, 33 percent cleionized water, and traces of preservatives such as methylparaben, and coloring matter. Parts and percentages given herein are by weight unless otherwise specified.

The capsules can be filled with any medicament which is stable to ionizing radiation and which does not dissolve or otherwise adversely afiect the gelatin. A suitable medicament especially useful for ophthalmic purposes has the following formulation:

Hydrocortisone acetate, fine powdered mg 15 Neomycin sulfate, powdered ..mg 6 Liquid Petrolatum U. S. P. (viscosity 180-200 sec onds Saybolt) percent 25 Wool fat U. S. P do 20 White petrolatum U. S. P q. s. to 1 gm.

According to one embodiment of the invention, the transparent envelope 14 is made of Saran, a transparent plastic sheet made of vnyl chloride-vinyldene chloride copolymer and the capsules are coated with a water-impervious material, such as varnish, lacquer, shellac, and the like.

In accordance with another embodiment of the invention, the transparent envelope 14 can be made of heatsealable, moisture-proof cellophane. Any of the wide variety of commercially available heat-sealable, moistureproof cellophane sheets can be utilized for this purpose. A suitable product is cellophane 300 MSAT made by E. I. du Pont de Nemours and Company which is made up of a regenerated cellulose sheet having a nitrocellulose moisture-proof coating topped with a waX coating. Other suitable grades of du Pont cellophane are 300 MST-57, 300 MSC and 300 MSRC. Other suitable beat-scaling, moisture-proof, transparent films can be prepared according to U. S. Patents 2,236,546, 2,32l,764, 2,430,726, and 2,354,060.

The following table illustrates the efiect of water-impervious coatings applied according to the invention on glycerol-fogging in radiation-sterilized packages. Each package was irradiated with 2 l0 volt electrons for a 2)(10 R. E. P.'s exposure.

It will be understood that the formulation given above is by way of illustration only and that any formulation which can be packaged in soft elastic, gelatin capsules and which can be safely sterilized by ionizing radiation are within the purview of the invention. If it is desired to use water-containing formulations, polyoxyalkylene ethers of alpihatic polyols may be incorporated in the formulation in accordance with U. S. Patent 2,667,268.

It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

I claim:

l. A radiation-sterilized package comprising a glycerolplasticized, soft elastic, gelatin capsule loosely enclosed in an hermetically-sealed envelope of transparent material, characterized by a film of moisture-impervious material between the inner surface of the envelope and the outer surface of the capsule which completely surrounds the capsule.

2. A radation-sterilized package comprising a glycerolplasticized, soft elastic, gelatin capsule loosely enclosed in an hermetically-sealed transparent envelope, characterized in that the entire inner surface of the envelope is coated with a water-impervious film.

3. A radation-sterilized package comprising a glycerolplasticized, soft elastic, gelatin capsule loosely enclosed in an hermetically-sealed transparent envelope, characterized in that the entire outer surface of the capsule is coated with a water-impervious film.

4. The package of claim 2 in which the transparent envelope is formed of heat-sealable, moisture-proof cellophane.

5. The package of claim 3 in which the coating or the capsule is phenol-forrnaldehyde resin varnish.

6. In a process for preparing sterile packages in which a glycerol-plasticized, soft elastic, gelatin capsule is hermetically sealed loosely in a transparent envelope and the resulting package sterilized by radiation, the method of preventing fogging of the transparent envelope as a result of the radiation sterilization which comprises hermetically scaling the glycerol-plasticized, soft elastic, gelatin capsule loosely in a transparent envelope with a continuous film of moisture-impervious material interposed between the inner surface of the envelope and the outer surface of the capsule and then subjecting the resulting package to radiation sterilization.

7. The process of claim 6 characterized in that the moisture-impervious film is a coating on the entire inner surface of the envelope.

8. The process of claim 6 characterized in that the moisture-mpervious film is a coating on the entire outer surface of the capsule.

9. The process of claim 8 in which the coating on the capsule is phenol-formaldehyde resin varnish.

10. In a proccess for preparing sterile packages in which a glycerol-plasticized, soft elastic, gelatin capsule is hermetically sealed in a transparent envelope and then sterilized by radiation, the method of preventing fogging of the transparent envelope as a result of the radiation sterilization which comprises hermetically sealing the glycerol-plasticized, soft elastic, gelatin capsule loosely in a transparent envelope formed of heat-sealable, moistureproof cellophane whereby a continuous film of moistureproof material is interposed between the inner surface of the envelope and the outer surface of the capsule and then subjecting the resulting package to radiation sterilization.

11. A package formed by hermetically scaling a glycerol-plasticized, soft elastic, gelatin capsule loosely in a transparent envelope With a continuous film of moistureimpervious material interposed between said capsule and said transparent material and subjecting the package to radiation sterilization, said radiation-sterlzed package being free of glycerol fogging.

12. The package of claim 11 in which the moistureimpervous film is a coatng on the entire inner surface of the envelope.

13. The package of claim 11 in which the moistureimpervious film is a coating on the entire outer surface of the capsule.

14. The process of claim 13 in which the coating on the capsule is phenol-formaldehyde resin varnish.

15. A package formed by hermetically scaling a glycerol-plasticzed, soft elastic, gelatin capsule loosely in a transparent envelope formed of heat-sealable, mostureproof cellophane whereby a continuous film of moisture- References Cited in the file of this patent UNITED STATES PATENTS 2,106,738 Harrson Feb. 1, 1938 2,512,367 Nicolle June 20, 1950 2,545,710 Snyder Mar. 20, 1951 2,635,742 Swartz et al. Apr. 21, 1953 2,667,268 Griffin Jan. 26, 1954 

1. A RADIATION-STERILIZED PACKAGE COMPRISING A GLYCEROLPLASTICIZED. SOFT ELASTIC, GELATIN CAPSULE LOSSELY ENCLOSED IN AN HERMETICALLY-SEALED ENVELOPE OF TRANSPARENT MATERIAL, CHARACTERIZED BY FILM OF MOISTURE-IMPERVIOUS MATERAIL BETWEEN THE INNER SURFACE OF THE ENVELOPE AND THE FIG -01 OUTER SURFACE OF THE CAPSULE WHICN COMPLETELY SURROUNDS THE CAPSULE. 